Chromatin and beyond: the multitasking roles for SIRT6

•The multiple roles for the mammalian deacylase SIRT6.•SIRT6 structure, enzymatic activity, and regulation.•SIRT6 function and impact upon human disease. In recent years there has been a large expansion in our understanding of SIRT6 biology including its structure, regulation, biochemical activity, and biological roles. SIRT6 functions as an ADP-ribosylase and NAD+-dependent deacylase of both acetyl groups and long-chain fatty-acyl groups. Through these functions SIRT6 impacts upon cellular homeostasis by regulating DNA repair, telomere maintenance, and glucose and lipid metabolism, thus affecting diseases such diabetes, obesity, heart disease, and cancer. Such roles may contribute to the overall longevity and health of the organism. Until recently, the known functions of SIRT6 were largely restricted to the chromatin. In this article we seek to describe and expand this knowledge with recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease.